Matt Hoffman

that has occurred over the course of the coronavirus disease 2019 (COVID-19) pandemic has shined an even brighter light on the already recognized care access challenges faced by patients with chronic, debilitating diseases such as multiple sclerosis (MS)—one that often requires repeat clinic visits and consults with a large team of health care professionals. With many of those visits now taking place virtually out of necessity, it has added support to the argument that there is a “clear and tremendous” need for more digital and telehealth-based interventions in MS.

This has long been the focus of clinical neuropsychologist Leigh Charvet, PhD, of the division of MS at NYU Langone Health in New York, who told 

that when these digital interventions are brought home to patients, clinicians reach a much broader spectrum of people living with MS—a highly important facet for research. Access to these resources, she said, underscores the demand for symptomatic management and rehabilitation, areas of treatment that often fall second to relapse prevention despite their immense impact on patient quality of life. To learn more about the digital therapeutic landscape and telemedicine’s place in the future treatment of MS, 

: Can you describe the evolution of your research into digital, home-based interventions for patients with MS?

: My entry into this world was with cognitive remediation, which we know that we need a lot of training to do. That’s probably one of the early therapies that has very well designed and accessible computer-based or online-based training. That was really our first entry into this, to send people computers to their home and supervise them remotely to complete our first trial. They did 60 sessions over 12 weeks, so you could just imagine that that wouldn’t have been able to be done if they were coming to clinic. In general, with cognition, we also think of what a lot of times we call the “invisible symptoms” that have such a burden on day-to-day living for so many people. That definitely includes fatigue, and things like pain, and emotional distress is another huge component for many of us. Our approach has been to evaluate computer-based or app-based interventions targeting these symptoms remotely, and we do that because we can reach many more people and provide the adequate number of treatment sessions.

Our particular focus moved from that cognitive rehabilitation trial to evaluating the use of noninvasive brain stimulation, in particular, something called transcranial direct current stimulation (tDCS). That’s in the world of noninvasive brain stimulation therapies, but it can be portable and wearable. We knew that we could reach people in their homes, so we developed a whole protocol where we do live video visits to help people self-administer, with supervision, tDCS. The idea with tDCS is it may be therapeutic on its own. For instance, it is approved in many countries for the treatment of depression, but we’re particularly interested in its ability to boost rehabilitative outcomes. The idea is that pairing the stimulation while you’re doing a training activity may boost the benefit of the training activity. We took our cognitive remediation that we had established and then added tDCS to that.

That also brought us into the world of some motor rehabilitation. For instance, there is an established at-home hand exercise program to strengthen and recover hand function, where we’re actually adding tDCS to that right now in the clinical trial. We’re also very interested in types of exercise, physical therapy, and aerobic exercise at home paired with the brain stimulation to see if we can boost the benefit of that training activity.

We’re interested in its benefits for fatigue, in general. There are a lot of parameters on how to use it, and in our research program, we’re sending it home. And with our absolutely amazing patient participants who are true collaborators, we’ve designed a platform where we can reach people in their homes and have the high volume of sessions and sample sizes needed to really evaluate these emerging therapeutics. In that work, what we’ve seen is that people are able to do what would seem on paper to be very complicated procedures in their homes with supervision. We’ve learned how to take on the technical burden on our side, and then guide people to be able to do these therapies very successfully in their homes.

How easily could these interventions be incorporated into standard care that patients with MS receive?

I think we’re pretty close to that, but there are a lot of these emerging therapeutics—and this is not specific to MS, especially as these things are computer-based—where there’s a disconnect between a provider or therapist telling a patient, “Here’s something that you can access that will help you,” and then the patient actually doing that. We all know that you should go to the gym every day, but if I don’t have a personal trainer or somebody watching me, I’m not going to do it. It’s hard to change the behavior. Because of the brain stimulation part with tDCS, we are live with patients through video visits every time. That’s really helped to have that behavioral adoption of the daily treatments, and I think that is a critical ingredient, that there is this supervised, connected onboarding of these daily therapies. There are all these wonderful tools out there, and many of them need more research, but the uptake is not there yet, and I think that connection is necessary for wider-scale adoption and people truly benefiting from these therapies.

What kind of barriers to adoption of these therapies have you experienced from both patients and the clinical community?

There are 2 types of pushback; 1 is awareness. Raising awareness for your patients of this tool does not mean that they’ll use it and benefit from it. That’s a common experience for a provider. Maybe [the provider] is aware of the tool, they refer their patients who then have the tool, but they hear, “Oh, I looked at it twice, and I didn’t do it.” There’s that critical period of structured onboarding, how to use it, in order to have an adequate evaluation. I think that causes premature dismissal of some things that are actually of great therapeutic benefit. Second, despite moving the dial on the acceptability of telehealth at a lightning rate because of COVID-19, there’s always been the pushback of “people can’t do that.” [Excuses like] my patient isn’t computer or tech savvy, or my patient has too much cognitive involvement or too many motor impairments to be able to do that. However, if you take care of designing the intervention, those are all easily overcome, and that’s what we found in our journey with our program.

Do you anticipate that more MS centers will adopt these interventions for at least some patients as they are validated?

Well, the short answer is absolutely. But I think what you raised is the critical piece, in terms of validation. What happens is, you have a glut of apps and online programs, and some are very science based. They take what we know from in-person therapy and make it into a digital therapeutic for access. Others are very different, and it’s hard for the consumer—it’s hard for the researcher—to tell the difference sometimes between what is what. We need carefully controlled clinical trials to guide our use because nobody wants to tell anybody to use something, to put the time into something, that hasn’t been demonstrated to be worth their time. I don’t think it would replace anything that we do now. We have our provider care, our nursing support, our social worker support, our therapists—physical, occupational, all kinds of therapists that we work with. That’s already comprehensive care on-site, but this would supplement it because we know that so many people in between these visits still have significant burden of disease, primarily with these symptoms for which there aren’t any tools to readily manage them. Therefore, access to these digital therapeutics might fill that need.

How might these digital and telehealth approaches influence data collection for the study of the MS population?

It will absolutely have a positive effect in getting therapies evaluated for what we call pragmatic practical use, so very downstream. For very good reasons, clinical trials have that rigorous enrollment eligibility criteria because it’s a different set of questions. We’re on the total opposite end of the spectrum in that we want to reach as many people living with MS as possible, to have these tools evaluated. Then we can see that maybe there’s a segment or something that wouldn’t benefit from them, but let us find out by including everybody. We’re much more focused on inclusion, and in that, we’ve been able to demonstrate that it’s very important for evaluation of these types of therapies—any kind of tele- or digital therapeutics—to include the broadest spectrum of people living with MS as possible. That’s important for so many reasons. There’s a segment of people living with MS who are left out of a lot of clinical trials right now, and they face even more burden to get to a clinic visit to receive some type of therapy for a trial. We’ve been encouraged by being able to reach so many more people than are typically reached in a clinical trial to evaluate these therapies.

Articles

As the adoption of telemedicine rises, the ability to incorporate digital and telehealth-based therapies offers clinicians a unique opportunity to supplement the comprehensive care model.

The Future Is Digital: Telemedicine Is Helping Open Doors to More Comprehensive Care in MS

This fall at the Alzheimer’s Drug Discovery Foundation (ADDF) International Conference, Ronald G. Crystal, MD, presented to more than 800 attendees on the current state of gene therapy for 

 influenced Alzheimer disease and other neurodegenerative disorders, detailing ongoing development and the current state of a small trial in patients with Alzheimer.

Crystal, who is the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, urged attendees to watch this therapeutic development closely, noting that the progress of gene therapy after decades of research reveals a promising future. With regard to Alzheimer, the plan is to provide the 

 gene—which literature has suggested may offer a protective effect against Alzheimer disease—to individuals who are 

, Crystal spoke to the takeaways for the clinical community and discussed the current state of that research. He also explained some of the challenges of developing these therapies, specifically as it relates to the differences in approach to intracellular versus extracellular targets.

: What are your thoughts are on the current state of gene therapy development?

 If you take the common neurodegenerative diseases and make a list of them, they have certain things in common despite the fact that they're very different diseases. One of the things that they have in common is that they are chronic diseases, right? They also, obviously, are in the nervous system and they have a therapeutic challenge—the blood-brain barrier. Those are 2 things that are key things that gene therapy can do. You can use gene therapy to have genes put directly into the nervous system, that bypasses the blood-brain barrier problem. Also, with gene therapy—if it works and if it's safe—there's a single administration to cure it forever. That's why so many people are interested, like us and many others.

We’re interested in gene therapy for the central nervous system. Now the issue is what's the state of the art and where are we? It started with us and some others approaching some diffuse diseases, like the lysosomal storage diseases, by taking the affected individuals to the operating room, putting Burr holes in the skull, catheters directly into the brain, and infusing the viruses that we use to carry the gene. But then the investigators start thinking, could you do this intravenously? That would obviously be a lot easier, right? Spinal muscular atrophy (SMA) was a good example of that. But the problem there was that even though it worked and it’s an approved therapy, is that it’s in infants before the blood-brain barrier is fully formed. With the blood-brain barrier fully formed, it's much tougher to use intravenous approaches because you think about how do the viruses get across the blood-brain barrier?

We and many others then started thinking about other strategies to deliver viruses to the brain. One approach was intraventricular: put a burr hole in the skull and a catheter directly into the cerebral spinal fluid in the ventricle. That's one approach. Then we started thinking about using intracisternal or intrathecal approaches, as well. That's evolving more as the favorite approach. Now, that doesn't mean it solves everything. But there's a lot of data in the field by many investigators, including us, that using intracisternal—or perhaps going down a little lower to C1, C2, or going down even lower and threading a catheter up—is another way to do it. If you can do that without toxicity, although there are some issues, you can get widespread expression throughout the brain. So that's been a part of a revolution in gene therapy for the CNS.

With regard to the viruses that are used, we think of those gene therapy terms as serotypes, and what is being used in the field is adeno-associated viruses (AAVs). There are some that are derived from humans, and some that are derived from nonhuman primates, and then there are some that are man-made in the laboratory by taking known ones and modifying the capsid. That’s done by sort of evolutionary techniques or directed techniques where you make specific changes. In the field, people are developing more capsids that may be a little better here and there, but I think in general, we have the capsids right. The strategy now is to use those capsids to choose the gene of interest and then the approach in terms of how we're going to deliver it.

Gene therapy for the CNS has really evolved over the last decade or so, and I think it's now at the point where there is obviously is an approved drug now, and I think you're going to see a number of approved drugs.

For neurodegenerative disease specifically, what are the challenges and what work are you and your colleagues doing?

In terms of the neurodegenerative diseases, the issues are with the hereditary disorders and the nonhereditary disorders and then sort of in-between disorders. The hereditary disorders like the lysosomal storage diseases, or the genetic form of ALS, or frontal temporal dementia, or Parkinson, or Huntington—you know what the target is. There becomes a delivery problem, a safety problem, an efficacy problem because you know you can deliver the gene, but can you accomplish it and do it sufficiently?

Then there's a group of disorders like we're interested in like Alzheimer, where we're taking advantage of the epidemiology that the apolipoprotein (

. Now, 85% of us are APOE3, but then if you're an 

 homozygote, you have a 15- to 20-fold increased risk for the development of Alzheimer, and if you develop it, it's more aggressive and occurs earlier as well. But if you're lucky enough to inherit from your parents 

, you have a decreased risk of Alzheimer, and if you do develop Alzheimer, it's milder and occurs later.

What got us interested in it was the heterozygotes. If you're an 

 takes away most of the risk—not entirely—for 

. APOE is made mostly by glia and astroglia, and the receptors are mostly on neurons. The particles are formed in the extracellular space. So, if you're heterozygote, your extracellular particles are 

heterozygotes. Our whole strategy is to bathe the brain of 

, so that the particles become heterozygote or even more 

. What we're doing is ignoring the pathogenesis of the disease, whether it's its amyloid, phospho-tau, inflammation, or multiple other mechanisms, all of which are being studied. We're proximal to that because we know that 

 affect multiple sites in the pathogenesis. That's the whole strategy. The way we're administering it is that we decided not to go intracisternal, we do it at C1 or C2. There is a sort of argument in the field about what's best. As you probably know, there are some blood vessels that run at the roof of the cisterna magna, so there's a little bit of a risk to going into the cisterna magna, so we decided to do C1 or C2, just below that. It's done under CT scanning, it's an outpatient procedure, and it takes about 25 to 30 minutes to place the needle, and about 5 minutes to administer. So far, we've treated 3 patients and we're looking for more, and we are actively following them.

What’s the takeaway for the clinical community from your perspective?

Gene therapy is essentially a drug delivery system. It's not an end-all, but it's a drug delivery system, just like small molecules are and monoclonal antibodies are. Gene therapy is real now. We and others have been working on it for several decades now. We now have approval for 1 drug in the field, and I think that one of the real challenges in neurodegenerative disease is the blood-brain barrier and that we can overcome that with the technology that we have. The questions are: can we do it safely, can we get enough in, and can we design the right targets?

What I'd want people to take away is to pay attention to the space. This is going to be something real, and there'll be select diseases where this will be a therapy that over the next decade will become real for you in terms of treating patients.

Ronald Crystal, MD, chairman, Department of Genetic Medicine, Weill Cornell Medicine, discussed the promise of gene therapy for patients with Alzheimer disease and related disorders.

Gene Therapy for Alzheimer and Neurogenerative Disease

An interim, 12-month analysis from the ongoing open-label extension study (NCT02510261) of patisiran (Onpattro; Alnylam) suggest that the therapy maintains its efficacy and an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy.

After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO (NCT01960348) and phase 2 open-label (NCT01961921) parent studies maintained their improvements on the modified Neuropathy Impairment Score +7 (mNIS+7), with mean changes of -4.0 (95% CI, -7.7 to -0.3) and -4.7 (95% CI, - 11.9 to 2.4), respectively. For those who were on placebo in APOLLO that switched in the open-label extension, the mean change from global OLE enrollment was -1.4 (95% CI -6.2 to 3.5).

The study was conducted by David Adams, MD, PhD, Head, French National Reference Centre for Familial Amyloidotic Polyneuropathy, and head, Department of Neurology Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, and a number of colleagues. “Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran,” they wrote.

Data from this extension were also presented at the 2018 AANEM Annual Meeting. The study includes 211 of 212 eligible patients enrolled between July 13, 2015, and August 21, 2017. In total, 137 were enrolled from the APOLLO patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. The data cutoff was September 24, 2018, at which time 126 (92%) from the APOLLO-patisiran group, 38 (78%) from the APOLLO-placebo group, and 25 (100%) from the phase 2 OLE patisiran group had completed 12-month assessments.

Centralizing Neuromuscular Disease Data With the MDA MOVR Database

“The global open-label extension is ongoing with no new enrollment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff,” Adams et al. wrote.

As for safety, 204 (97%) of the overall cohort reported adverse events (AEs), and the most common treatment-related AE reported was mild or moderate infusion-related reactions.

There were 82 (39%) patients who reported a serious AE, and 23 (11%) deaths. The APOLLO placebo group experienced a higher frequency of serious AEs (28 of 49; 57%) than the APOLLO patisiran group (48 of 137; 35%) or the phase 2 open-label extension group (6 of 25; 24%). The frequency of deaths in the global cohort was higher in the APOLLO-placebo group (13 of 49; 27%), who had a higher disease burden than the APOLLO-patisiran (10 of 137; 7%) and phase 2 OLE patisiran (0 of 25; 0%) groups.

The median age of patients in the extension trial was 64 years, and 74% were male. The mean time since hATTR amyloidosis diagnosis to first patisiran dose was 2.9 years. Overall, 54% of patients had a non-V30M transthyretin (TTR) genotype and 52% were enrolled in Western Europe. The most common polyneuropathy disability scores were II (27%) and IIIA/B (41%). The mean baseline mNIS+7 was 77, which was driven primary by those enrolling from the placebo arm of the APOLLO study who entered with an mNIS+7 of 101.

Patients switching from placebo to patisiran experienced robust reductions in serum TTR levels. By week 6 of the extension studies, mean serum TTR levels had decline by 79% for patients receiving patisiran for the first time. TTR levels were maintained in the extension study for those treated with the RNA inhibitor in the phase II trial and APOLLO, even out to 4 years, showing the durability of benefit.

In the APOLLO study, which led to the FDA approval of patisiran for hATTR amyloidosis in August 2018, the least mean square change in mNIS+7 from baseline for those treated with patisiran was -6.0 (±1.7) versus 28.0 (±2.6) with placebo.

 Following 52 weeks of treatment with patisiran in the extension study, patients originally treated with the RNA inhibitor had sustained improvements in neuropathy, and those initially receiving placebo experienced a rapid halting disease progression.

REFERENCE
1. Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Published online November 16, 2020. doi: 10.1016/S1474-4422(20)30368-9
2. Gonzalez-Duarte A, Coelho T, Adams D, et al. Long-term use of patisiran, an investigational RNAi therapeutic, in patients with hereditary transthyretin-mediated amyloidosis: 12 month efficacy and safety from global open-label extension study. Presented at: 2018 AANEM Annual Meeting, National Harbor, MD, October 10-13, 2018. Abstract 10
3. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. 

After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO and phase 2 open-label parent studies maintained their improvements on the modified Neuropathy Impairment Score +7.

Patisiran Shows Sustained Long-Term Efficacy in Patients With hATTR

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The Mind Moments podcast features exclusive interviews with leaders in the field discussing the latest research and disease management strategies across the breadth of neurology, including epilepsy, multiple sclerosis, Parkinson disease, dementia, sleep disorders, and more.

Episode 22, "Capitalizing on Collaboration in Neurology Care," features an interview with Paul Fisher, MD, professor of neurology, and chief of child neurology, and Gerald Grant, MD, FACS, endowed professor of neurosurgery, and chief of pediatric neurosurgery, both of the Brain and Behavior Center at Stanford Children’s Health. The pair discussed how their team at the center is bolstering the use of multidisciplinary care and harnessing advances in science to improve the care of children with neurologic disease. Specifically, they spoke to how Stanford Children's Health collaborates across departments and specialties—from neurology to neurosurgery, radiology, nursing, and pathology, among others—as well as its utilization of the technology, talent, and expertise available from the neighboring Stanford Health Care and Stanford University School of Medicine. The model, they noted, is designed in both actions and geography to do pediatrically what Stanford routinely offers for adults.

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Podcasts

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Paul Fisher, MD, and Gerald Grant, MD, FACS.

Matt Hoffman

Articles

The Future Is Digital: Telemedicine Is Helping Open Doors to More Comprehensive Care in MS

Gene Therapy for Alzheimer and Neurogenerative Disease

Patisiran Shows Sustained Long-Term Efficacy in Patients With hATTR

Episode 22: Capitalizing on Collaboration in Neurology Care